7. Project Summary/Abstract Worldwide, about eleven million burn injuries occur per year. According to CDC, at least one fire related injury is reported every 30 minutes in the United States. Patients with over 10% total body surface area burn suffer from anemia of critical illness. Anemia in burn and trauma patients is largely multifactorial requiring multiple transfusions. Approximately 12 million units of packed red blood cells (pRBCs) are transfused each year in the United States. Emerging evidences around the globe indicate transfusion risks outweigh benefits in the critically ill burn patients and transfusions >4 units of blood is an independent risk factor for systemic infections. Particularly in patients with major burns, the number of transfusions is associated with mortality and infectious episodes. Despite the adverse consequences of transfusion, lack of a reliable test platform to study the molecular mechanisms of impaired erythropoiesis in burn patients has been a limiting factor to consider alternate treatment strategies. Our laboratory is beginning to underpin the molecular and neuronal responses as a possible etiology in burn patients who suffer from persistent anemia in spite of elevated erythropoietin (Epo) levels. Recent evidences from our laboratory indicate that resistance to Epo in experimental mice and burn patients is due to decrease in the number of bone marrow progenitors that can produce red blood cells (erythroid) and that beta-adrenergic blockade following burn while improves early erythroid progenitors, does not improve peripheral blood Hgb. This observation steered us to establish that late stage erythroblast maturation is affected after burn. Maturation is the process of enucleation upon which the mature reticulocytes leave the bone marrow to occupy peripheral circulation. We believe that in burn patients, both the early progenitor production and late maturation stages of RBC production are affected causing them to be anemic. We developed an animal model and an innovative culture system to validate our findings in blood samples obtained from burn patients. Thus far, our results bring to light that discrete ?2- and ?3-adrenergic mechanisms regulate early and late erythropoiesis in burns providing a framework for further investigations. A molecular chaperone called alpha hemoglobin stabilizing protein (Ahsp) in nucleated erythroblasts is found essential for effective hemoglobin assembly and prevents apoptosis. Also, a central erythroblast island (EBI) macrophage is vital for iron transfer and to engulf the ejected nucleus. Taken together, our overarching hypothesis is that anemia of critical illness is caused by elevated catecholamine after burn injury, which lowers Ahsp in multi potential progenitors through ?2-receptor action and synergistically provokes ?3- adrenergic receptor mediated depletion of bone marrow EBI macrophages disrupting terminal maturation of erythrocytes. Overall, results gleaned from the experimental model combined with clinical data will provide the mechanistic insight into post burn anemia, which will open up potentially targetable opportunity for therapeutic interventions aimed at anemia of critical illness and reduce transfusion needs.